Although the carcinogenic effect of ionizing radiation has been known for a number of years and detailed studies of the lethal effects of low doses of radiation in cultured mammalian cells, including diploid human cells, have been carried out, few investigations have quantitated the frequency of mutations induced in diploid human fibroblasts with low doses of ionizing radiation and only two reports have appeared of neoplastic transformation of diploid human cells in culture by such radiation. These latter studies did not include a dose-response nor an investigation of the role of DNA repair in protecting cells from the transforming effect of the radiation. We have recently developed a reproducible, quantitative assay for carcinogen-induced neoplastic transformation of diploid fibroblasts derived from normal or cancer-prone individuals whose cells are deficient n DNA repair. Exposure of the cells to carcinogens yields a linear, dose dependent increase in the frequency of anchorage-independent cells (capable of forming colonies in soft agar) and cells from these colonies invariably form fibrosarcomas in athymic mice. We have also developed reproducible quantitative assays for measuring carcinogen-induced increases in the frequency of mutations in diploid human cells (resistance to thioguanine and to diphtheria toxin) and have used it to demonstrate repair of potenitally mutagenic damage by human cells in culture. We propose to use these assays to (1) determine the response of diploid human fibroblasts to the transforming action of low doses of ionizing radiation, (2) measure the dose-response of the same irradiated population to the mutagenic effect of radiation using the two genetic markers, (3) see whether fractionating the doses significantly alters the frequency of radiation-induced neoplastic transformation and/or mutation, (4) determine whether repair of potenitally lethal damage alters the frequency of transformation and/or mutation in these human cells. Finally, we will determine if cells derived from persons with certain cancer-prone syndromes, which have been shown to be abnormally sensitive to the lethal effect of ionizing radiation or defective in repair of radiation-induced lesions, are abnormally susceptible to the transforming and/or mutagenic effects of radiation. The results we obtain with the latter cells will be compared to those obtained with the normally-reparing cells to gain insight into the role of repair in protecting human cells from such radiation and to determine possible causes of the cancer-proneness of these patients: viz., (a) ataxia telangiectasia, (b) retinoblastoma, (c) Fanconi's anemia, and (d) a particular xeroderma pigmentosum patient.